The growth and development of the placenta is dependent upon expansion and lineage specific differentiation of a population of stem cells referred to as trophoblast stem (TS) cells. Self-renewal of TS cells and differentiation are controlled by a network of transcriptional regulators. Chromatin reorganization, remodeling and epigenetic changes play a fundamental role in the regulation of gene expression during cell differentiation. Special AT-rich sequence binding protein 1 (SATB1) and SATB2 act as chromatin organizers as well as transcriptional regulators of tissue specific genes. SATB proteins bind to specific matrix attachment regions of DNA, recruit chromatin-remodeling enzymes, and interact with the required transcriptional machinery resulting in gene activation or gene repression. They participate in transcriptional regulation of key genes controlling the differentiation of T lymphocytes, osteoblasts, cortical neurons, and embryonic stem cells. The trophectoderm layer of cells in the mouse embryo express high levels of SATB proteins. Expression of these genes diminishes in the placenta with progression of gestation, which coincides with the disappearance of the TS cell population. Our initial in vivo analyses of placentas possessing Satb1 and/or Satb2 null mutations suggest that SATB1 and SATB2 are essential for normal placental development. Both of these chromatin regulators are preferentially expressed in mouse TS cells and downregulated as trophoblast cells differentiate. Preliminary in vitro 'loss-of-function' studies indicate that SATB1 and SATB2 regulate TS cell renewal and differentiation. We propose that SATB proteins play critical roles in regulating self-renewal of TS cells and controlling trophoblast differentiation by activating key genes required for TS cell self-renewal or by repressing genes leading to TS cell differentiation. We plan to examine the role of SATB proteins during placental development in mice and in TS cell culture models. These experiments will lead to the identification of molecular mechanisms controlling TS cell homeostasis and placental development. Revealing the fundamental regulators of TS cells will greatly expand our understanding of placental morphogenesis and the pathophysiology of placenta-associated disorders.